Myeloid Bmal1 Deletion Promotes Hypertension and Hypertension-associated Vascular Remodeling in Mice

[Speaker] Mingyu Huo:1
[Co-author] Hongsong Zhang:1, Danyang Tian:1, Chi Wai Lau:1, Yalan Wu:1, Ajay Chawla:2, Yu Huang:1, Xiao Yu Tian:1
1:School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, 2:Cardiovascular Research Institute, University of California San Francisco, USA

The molecular clock plays an essential role in regulating cardiovascular function and immune responses through rhythmic expression of clock controlled transcripts and their biological functions. Our previous study showed that myeloid specific deletion of Bmal1 promotes atherosclerosis in ApoE knockout mice by enhancing monocyte trafficking to plaques. The role of Bmal1 in vascular inflammation in hypertension is unknown.
We propose that Bmal1 contributes to vascular inflammation and immune cell infiltration in the adventitia thus accelerates hypertension, while also promotes renal inflammation and dysfunction.
We use the Bmal1 FloxP/FloxP (Bmal1MWT) as control and Bmal1 FloxP/FloxP, LysM Cre/+ (Bmal1MKO) as myeloid specific Bmal1 deficient mice housed under 12 hour light and dark cycle at 22 degree. Hypertension was induced by angiotensin II infusion via osmotic pump for 28 days and blood pressure was measured using CODA tail-cuff system and implantable radio telemetry.
We found higher systolic blood pressure (131.5 vs 117.8 mmHg) in Bmal1MKO compared to Bmal1MWT mice after angiotensin II infusion. Flow cytometric analysis showed more total macrophages and more Ly6c macrophages in the kidney from Bmal1MKO mice. Endothelium dependent vasodilation in mesenteric arteries and endothelium dependent contraction in carotid arteries were further impaired in hypertensive Bmal1MKO mice, indicating Bmal1 deletion promotes hypertension induced vascular dysfunction. Masson's trichrome staining of aorta showed thicker tunica media and higher media-to-lumen ratio with more macrophages infiltration in the adventitia in Bmal1MKO mice after angiotensin II infusion. The mRNA expressions of MMP9 and MMP13 in aorta from Bmal1MKO mice were much higher, meaning that imbalance of extracellular matrix induced by upregulation of MMPs played important roles in vascular remodeling and dysfunction.
Our results indicate myeloid Bmal1 deletion exacerbates hypertension and hypertension induced vascular inflammation. Further experiments will be carried out to examine the mechanisms between Bmal1 and MMPs in the development of vascular remodeling in hypertensive mice.
Supported by China NSFC 9173910019, Hong Kong Health Bureau HMRF RFS 01150057.
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